ORGAN VARIATION IN THE MUTAGENICITY OF DIMETHYLNITROSAMINE IN BIG BLUE(R) MICE

Organ specificity in the lacl mutant frequency (MF) induced by dimethy lnitrosamine (DMN) was analyzed in lung, liver, kidney, bone marrow, u rinary bladder, and testis of Big Blue(R) mice. Cell proliferative act ivity was also analyzed in some of these tissues by immunohistochemica l staining of proliferating cell nuclear antigen (PCNA). Clastogenicit y of DMN was concomitantly analyzed by the peripheral blood micronucle us assay with the same animals used for the lacl mutation assay. Five daily intraperitoneal (ip) treatments with DMN (1 mg/kg) increased MF in liver (6.2 x control), kidney (2.4 x control), and lung (2.1 x cont rol). These are known target organs for DMN carcinogenesis. No MF incr ease was observed in nontarget organs studied, i.e., bone marrow, blad der, and testis. Single ip treatment with DMN also increased lacl MF i n liver but the increases were smaller than in a 5-daily-treatment reg imen. This result suggests that multiple dosing is more effective in t he transgenic mutation assay. The enhancement of cell proliferation ob served was in bronchial epithelia 7 days after treatment. No micronucl eus induction in peripheral blood was observed 24 hours after 2 and 3 daily ip treatments with 1 mg/kg DMN. An increase in the incidence of micronucleated reticulocytes in peripheral blood was observed 48 hours after single ip treatment with 5 or 10 mg/kg DMN, The present study d emonstrated organ-specific induction of gene mutations by DMN, which s uggests a relevance of this assay for the prediction of organ-specific carcinogenesis. (C) 1996 Wiley-Liss, Inc.